LHRH antagonists having improved solubility properties

Abstract

The invention relates to peptides which contain N-methylated amino acid units and have improved water solubility. Medicaments in which the peptides according to the invention are contained can be used for the treatment of hormone-dependent tumors and hormone-influenced non-malignant disorders.

1. A compound of the general formula I
   A-Xxx 1 -Xxx 2 -Xxx 3 -Xxx 4 -Xxx 5 -Xxx 6 -Xxx 7 -Xxx 8 -Xxx 9 -Xxx 10 -NH 2   (I) 
 
       in which:
 A is an acetyl or a 3-(4-fluorophenyl)propionyl group, 
 Xxx 1  is D-Nal(1) or D-Nal(2), 
 Xxx 2 -Xxx 3  is D-Cpa-D-Pal(3) or a single bond, 
 Xxx 4  is Ser, 
 Xxx 5  is N-Me-Tyr, 
 Xxx 6  is D-[ε-N′-(imidazolidin-2-on-4-yl)formyl]-Lys, D-(3-amino-1,2,4-triazole-3-carbonyl)-Lys, or D-[ε-N′-4-(4-amidino-phenyl)amino-1,4-dioxobutyl]-Lys, 
 Xxx 7  is Leu or Nle, 
 Xxx 8  is Arg or Lys(iPr), 
 Xxx 9  is Pro, and 
 Xxx 10  is Ala, D-Ala, or Sar, 
 
       and their salts with pharmaceutically acceptable acids. 
     
     
       2. The compound according to  claim 1 , wherein the salt is an acetate, trifluoroacetate, or embonate. 
     
     
       3. Method of treating prostate carcinoma or breast cancer comprising administering an effective amount of compound of the general formula I
   A-Xxx 1 -Xxx 2 -Xxx 3 -Xxx 4 -Xxx 5 -Xxx 6 -Xxx 7 -Xxx 8 -Xxx 9 -Xxx 10 -NH 2   (I) 
 
       in which:
 A is an acetyl or a 3-(4-fluorophenyl)propionyl group, 
 Xxx 1  is D-Nal(1) or D-Nal(2), 
 Xxx 2 -Xxx 3  is D-Cpa-D-Pal(3) or a single bond, 
 Xxx 4  is Ser, 
 Xxx 5  is N-Me-Tyr, 
 Xxx 6  is D-[ε-N′-(imidazolidin-2-on-4-yl)formyl]-Lys, D-(3-amino-1,2,4-triazole-3-carbonyl)-Lys, or D-[ε-N′-4-(4-amidino-phenyl)amino-1,4-dioxobutyl]-Lys, 
 Xxx 7  is Leu or Nle, 
 Xxx 8  is Arg or Lys(iPr), 
 Xxx 9  is Pro, and 
 Xxx 10  is Ala, D-Ala, or Sar, 
 
       and their salts with pharmaceutically acceptable acids to an individual in need thereof. 
     
     
       4. Method of treating benign prostate hyperplasia or endometriosis comprising administering an effective amount of compound of the general formula I
   A-Xxx 1 -Xxx 2 -Xxx 3 -Xxx 4 -Xxx 5 -Xxx 6 -Xxx 7 -Xxx 8 -Xxx 9 -Xxx 10 -NH 2   (I) 
 
       in which:
 A is an acetyl or a 3-(4-fluorophenyl)propionyl group, 
 Xxx 1  is D-Nal(1) or D-Nal(2), 
 Xxx 2 -Xxx 3  is D-Cpa-D-Pal(3) or a single bond, 
 Xxx 4  is Ser, 
 Xxx 5  is N-Me-Tyr, 
 Xxx 6  is D-[ε-N′-(imidazolidin-2-on-4-yl)formyl]-Lys, D-(3-amino-1,2,4-triazole-3-carbonyl)-Lys, or D-[ε-N′-4-(4-amidino-phenyl)amino-1,4-dioxobutyl]-Lys, 
 Xxx 7  is Leu or Nle, 
 Xxx 8  is Arg or Lys(iPr), 
 Xxx 9  is Pro, and 
 Xxx 10  is Ala, D-Ala, or Sar, 
 
       and their salts with pharmaceutically acceptable acids to an individual in need thereof.